We used the oxygen/glucose deprivation (OGD) model of ischemia in corticostriatal brain slices to test the hypothesis that metabolic deficiencies in R6/2 transgenic Huntington's disease (HD) mice will impair their recovery from an ischemic challenge. Corticostriatal extracellular field excitatory postsynaptic potentials (fEPSPs) were evoked in transgenic and wildtype (WT) mice in three age groups; 3-4 weeks, before the overt behavioral phenotype develops, 5-9 weeks, as overt behavioral symptoms begin and 10-15 weeks when symptoms were most severe. OGD for 8 min completely and reversibly inhibited fEPSPs. Although responses of 3-4 week WTs showed a tolerance to ischemia and recovered rapidly, ischemic sensitivity developed progressively, and at 5-9 and 10-15 weeks responses recovered more slowly from OGD. In contrast, while 3-4 week R6/2 transgenic fEPSPs showed significantly more ischemic sensitivity than their WT counterparts, the R6/2 fEPSPs maintained a relative tolerance to ischemia at 5-9 and 10-15 weeks. As a result, a "crossover" point occurred, roughly coinciding with the development of the overt behavioral phenotype (5-9 weeks), after which time R6/2 fEPSPs were significantly more resistant to ischemia than WT responses. The increased ischemic sensitivity in 3-4 week R6/2 responses was not due to excessive glutamate release during OGD, as it persisted in the presence of the glutamate receptor antagonist kynurenic acid (1mM). While the mechanism for development of ischemic resistance in R6/2 transgenics remains unknown, it correlates with metabolic and biochemical changes described in this model and in HD patients.